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Title: Exploring the mechanisms of synaptotropic arbor growth in Drosophila
Author: Constance, William Duncan
ISNI:       0000 0004 7656 3440
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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The role of synapses as junctions of information transfer is well understood, however the exact role they play in the early development of neuronal arborisations is unclear. Studies in the vertebrate central nervous system (CNS) by Vaughn led him to posit the ‘synaptotropic hypothesis’ whereby the stabilisation of exploratory filopodia/branches is strongly correlated with nascent synapse formation. By pioneering a novel in vivo system, I have been able to show for the first time in Drosophila that the growth of complex arborisations occurs by synaptotropic-like mechanisms. Using live imaging during the pupal stages I see that the elaborate axonal arborisations of pleural motoneurons are built by dynamic interactions with their postsynaptic partners. Fluorescently labelled proteins show that this process involves the early assembly of synaptic components at sites of growth and branching. Using two independent binary expression systems to live image the pre- and postsynaptic elements I see a complementary pairing of hemi-synapses during growth. Arbor growth requires the trans-synaptic signalling of the synaptic cell adhesion molecules Nlg/Nrx which selectively stabilise exploratory axonal branches. Whole null mutants and local manipulations show that signalling through these molecules directs growth in a tropic manner. Published data on arbor growth in the Xenopus visual system forwards that Nlg/Nrx signalling is required for synapse formation, which in turn allows synaptic activity to stabilise branches. Using calcium imaging, in combination with pharmacological approaches, I have mapped the development of activity in my system. By silencing neurotransmission using TTX and single cell genetic mosaic approaches I find that the growth of these arborisations occurs without activity. Taken together these data point toward an important activity-independent role for proto-synapses during the development of arbor shape. These findings point to a mechanism of complex arbor construction from a simple iterated program of development, the principles of which may be evolutionarily conserved across taxa. Since arbor growth defects are associated with a number of neurodevelopmental disorders, such a model for this mode of growth in a genetically tractable system like the fly could have important implications for therapeutic research.
Supervisor: Williams, Darren ; Andreae, Laura Christiana ; Tear, Guy Justin Clive Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available